The present invention relates to the field of electrochemical carboxylation synthesis.
Serotonin is a biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.
Serotonin receptors are cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behaviour of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action.
It is been disclosed that compounds like spiro-[9,10-dihydroanthracene]-9,3′-pyrrolidine (SPAN) and derivatives thereof are selective serotonin receptor antagonist (5-HT). By antagonist of serotonin receptors is meant compounds that block the action of endogenous serotonin at the receptor and prevent its activation. These compounds are useful as antidepressant and anti-anxiety agents and are of pharmacological interest.
There are several known serotonin receptors and types of antagonists currently used.
For example, serotonin 5-HT1 receptors are in the central nervous system. An excess of serotonin availability at the serotonin 1 A receptor causes serotonin syndrome. Agonists of serotonin 5-HT1 D, such as sumatriptan, are used to treat migraine headaches.
As for serotonin 5-HT2 receptors, antagonists, such as risperidone, are used to treat schizophrenia. Their agonists, such as fluoxetine, are used to treat depression. Agonists of the 5-HT2C receptor, such as lorcaserin, decreases appetite via the proopiomelanocortin system. However, non-selective activation of the 5-HT2B receptors as well as the 5-HT2C receptors by fenfluramine and dexfenfluramine may damage heart valves via agonism of 5-HT2B receptors on valvular cells.
As for serotonin 5-HT3 receptors, they stimulate gastrointestinal motility. Antagonists, such as ondansetron, are used as an antiemetic for chemotherapy. Antagonists, such as alosetron, are to treat diarrhea-predominant irritable bowel syndrome.
U.S. Pat. No. 6,806,283 (Glennon et al.) discloses the use of SPAN as selective serotonin receptor antagonists and methods of their use as anti-depressant and anti-anxiety agents. Different synthesis routes for obtaining of SPAN and other derivatives are also disclosed, although none of electrochemical type.
Due to the importance of these compounds as anti-depressant and anti-anxiety agents it would be of great help to have alternative advantageous routes for obtaining said compounds.
The present inventors have surprisingly found an alternative synthesis route for obtaining SPAN and derivatives thereof by applying a step of controlled potential electrolysis on the starting material under CO2 atmosphere. Advantageously, as a result of this step new intermediates have also been found.
Electrochemical carboxylation is a chemical reaction already used in the synthesis of chemical compounds.
Thus, U.S. Pat. No. 5,089,661 discloses the synthesis of a 2-aryl-propionic acids having anti-inflammatory properties using electrocarboxylation for the synthesis of the starting salt. U.S. Pat. No. 4,072,583 reports on the electrolytic carboxylation of carbon acids via electrogenerated bases leading to carboxylated carbon acids. Also U.S. Pat. No. 4,708,780 discloses a process for electrocarboxylating carbonyl compounds from CO2 for the production of α-hydroxycarboxylic acids.
The disclosure of the previously identified patents is hereby incorporated by reference.
In view of the prior art, there is still the need for finding new advantageous routes for obtaining SPAN and derivatives thereof. None of the previous documents discloses or suggests a synthesis route based on electrochemical carboxylation for obtaining new or not new intermediates which in turn are useful for obtaining SPAN and derivatives thereof.